2,3,4,5 - tetrahydro-3-hydroxy-6-phenyl-2-sulfonylpyridazine - 3 - propionic acid gamma-lactones and congeners

ABSTRACT

DISCLOSED HEREIN ARE ANALGESIC, ANTI-ULCEROGENIC, AND ANTI-PROTOZOAL 2,3,4,5-TETRAHYDRO-3-HYDROXY-6-PHENYL-2SULFONYLPYRIDAZINE-3-PROPIONIC ACID $-LACTONES AND CONGENERS; ANTI-ULCEROGENIC, PEPSIN-INHIBITING; ANTI-BACTERIAL, AND ANTI-PROTOZOAL 5-PHENYL-1-SULFONAMIDOPYRROLE-2-PROPIONIC ACIDS AND CONGENERS; AND THE PREPARATION OF THESE COMPOUNDS FROM CORRESPONDING 4,7-DIOXOHEPATIONIC ACIDS AND SULFONIC ACIDS HYDRAZIDES.

United States Patent 2,3,4,5 TETRAHYDRO-3-HYDROXY-6-PHENYL-2- SULFONYLPYRIDAZINE 3 PROPIONIC ACID 'y-LACTONES AND CONGENERS William K. Spreuger, Niles, lll., assiguor to G. D. Searle & Co., Chicago, Ill.

No Drawing. Continuation-impart of application Ser. No. 53,335, July 8, 1970. This application July 31, 1970, Ser. No. 60,113

Int. Cl. C07d 51/04 US. Cl. 260-250 A 17 Claims ABSTRACT OF THE DISCLOSURE Disclosed herein are analgesic, anti-ulcerogenic, and anti-protozoal 2,3,4,5-tetrahydro 3 hydroxy-6-phenyl-2- sulfonylpyridazine-3-propionic acid 'y-lactones and congeners; anti-ulcerogenic, pepsin-inhibiting; anti-bacterial, and anti-protozoa] 5-phenyl-1-sulfonamidopyrrole-2-propionic acids and congeners; and the preparation of these compounds from corresponding 4,7-dioxoheptanoic acids and sulfonic acid hydrazides.

The application for Letters Patent securing the invention herein described and claimed is a continuation-in-part of applicants prior co-pending application Ser. No. 53,335, filed July 8, 1970.

This invention relates to 2,3,4,5-tetrahydro-3-hydroxy- 6-phenyl-2-sulfonylpyridazine-3-propionic acid 'y-lactones and congeners, and to processes for the preparation thereof. More particularly, this invention provides new, useful, and unobvious chemical compounds of the formula wherein Ph represents phenyl optionally substituted by lower alkyl, lower alkoxy and/or halogen and Z represents lower alkyl or phenyl, the latter optionally substituted by lower alkyl, lower alkoxy, halogen, and/or nitro. From 1 to as many as 5 of the aforesaid optional substituents, alike or dilferent, can be present; and their positioning about the involved benzene rings is not critical.

The lower alkyls comprehended by Ph and Z are typically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.- butyl, tert.-butyl, pentyl, neopentyl, hexyl, isohexyl, and like monovalent, saturated, acyclic, straightor branchedchain hydrocarbon groupings of the formula wherein n represents a positive integer less than 8. The lower alkoxys comprehended by Ph and Z are defined by the expression -0lower alkyl wherein lower alkyl has the meaning assigned above.

The compounds to which this invention relates are useful by reason of their valuable biological properties. Thus,

A pressure-standardized artery clip is placed 1 inch from the base of the tail of each of a group of adult, male, albino, Charles River mice weighing 18-25 gm.; and 10 animals are selected therefrom which respond to the clip by turning, biting, or the like within 15 sec. The response times for these 10 animals are recorded, the clips are removed, and 50 mg. per kg. of test compound is thereupon administered to each animal via intraperitoneal injection. Solid compounds are prepared for injection by mixing 25 mg. with approximately 0.2 ml. of a 50:50 (by volume) mixture of propylene glycol and Tween 80, then diluting to 5 ml. with water and homogenizing; liquid compounds are prepared by warming 25 mg. with 1 ml. of 50:50 (by volume) propylene glycol and Tween 80, then diluting to 5 ml. with aqueous 10% gum acacia. At 30-min. intervals during the 2 hr. immediately following administration, the clips are replaced on the tails for a maximum of 30 sec. in each instance, during which response times are recorded as before. If, at one or more intervals, response times for at least half of the animals are more than twice as long as prior to compound administration, the compound is considered to be analgesic.

The anti-ulcerogenic utility of the instant compounds is evident from the results of a standardized test carried out as described in US. 3,483,192.

The anti-protozoal utility of the instant compounds is evident from the results of a standardized test for their capacity to immobilize Tetrahymena pyriformis. In this test, a nutrient broth consisting of 12 gm. of proteose peptone, 8 gm. of sucrose, and 500 ml. of water is sterilized and inoculated with 10% (by volume) of an axenic culture of T. pyriformis. Meanwhile, compound is heated in sterile distilled water at a concentration of 2000 per ml. and a temperature of C. for 20 min. An equivolume mixture of this compound preparation and the inoculated medium is incubated aerobically at 32 C. for 48 hr. and then examined microscopically for the presence of motile tetrahymena. If any are observed, the compound is considered inactive. If no motile tetrahymena are observed, the incubated mixture is serially diluted and mixed with an inoculated medium of the same composition as that described above excepting that 1000 parts of distilled water instead of 500 parts and 5% (by volume) of the culture instead of 10% are incorporated. Amounts of the latter medium added are such that concentrations of 100, 10, and 17 of compound per ml. result. The mixtures thus obtained are incubated as before and then examined microscopically for motile tetrahymena. Potency is expressed as the minimum concentration at which no motile tetrahymena are discernible. Controls are provided by com current incubations identical with the foregoing except for the absence of compound.

Those skilled in the art will recognize that observations of activity in standardized tests for particular biological effects are fundamental to the development of valuable new drugs, both veterinary and human.

Preparation of the subject compounds proceeds by heating a 4,7-dioxoheptanoic acid of the formula PhCOCH- CH COCH CH COOI-I with a sulfonic acid hydrazide of the formula ZSO NHNH [Ph and Z being defined as before], using benzene as the reaction medium and p-toluenesulfonic acid monohydrate as a condensing agent. The resultant 2,3,4,5-tetrahydro-3-hydroxy-2-sulfonylpyridazine-3-propionic acid '7- lactones are isolated by stripping the solvent and washing the residue thoroughly with aqueous sodium bicarbonate.

From the bicarbonate washes, on precipitation with excess hydrochloric acid and Fischer Speier esterification,

S- henyl-1-sulfonamidopyrrole-2-propionic acids and congeners of the formula lIIHSOzZ N Flu-W Wcmcmooon [Ph and Z being defined as before and R representing hydrogen or lower alkyl] useful by reason of their valuable pepsin-inhibiting, anti-ulcerogenic, anti-bacterial, and antiprotozoal properties are obtained as by-products. These by-products are not, for the most part, analgesic.

The pepsin-inhibiting utility of the by-products is evident from the results of a standardized test carried out as described in US. 3,475,420, and their anti-ulcerogenic utility and anti-protozoal utility in respect of T. pyriformis is evident from the results of the standardized test described hereinbefore. Evidence of their anti-bacterial utility in respect of Diplococcus pneumoniae and their antiprotozoal utility in respect of T. gelleii is provided by the results of tests carried out as described in US. 3,483,192. The anti-bacterial utility of the aforesaid by-products is further evidenced by the results of a standardized test for their capacity to prevent the growth of Erwinia sp. In this test, nutrient broth (manufactured by Baltimore Biological Laboratories or Difco) is prepared at twice the concentration recommended by the manufacturer, sterilized, and inoculated with 2% (by volume) of a culture of Erwinia sp. Meanwhile, compound is heated in sterile distilled water at a concentration of 2000 per ml. and a temperature of 80 C. for 20 min. An equivolume mixture of this compound preparation and the inoculated broth is incubated aerobically at 37 C. for 24-48 hr. and then examined grossly for growth of the test organism. If such growth is observed, the compound is considered inactive. If no growth is observed, the incubated mixture is serially diluted and mixed with an inoculated broth of the same composition as before excepting that the concentration is halved and 1% (by volume) of the culture instead of 2% is incorporated. Amounts of the latter broth are added such that concentrations of 100, 10, and 17 of compound per ml. result. The mixtures thus obtained are incubated as before and then examined grossly for growth of the test organism. Potency is expressed as the minimum concentration at which no growth of test organism is discernible. Controls are provided by concurrent incubations identical with the foregoing except for the absence of compound.

The following examples describe in detail compounds illustrative of the present invention, methods which have been devised for their preparation, and by-products thereof. It will be apparent to those skilled in the art that many modifications both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 2,3,4,5 tetrahydro 3 hydroxy-2-methylsulfonyl-6- phenylpyridazine-3-propionic acid 'y-lactone and l-methanesulfonamido-S-phenylpyrrole-Z-propionic acid: A mixture of 94 parts of 4,7-dioxo-7-phenylheptanoic acid, 44 parts of methanesulfonic acid hydrazide, 1 part of p-toluenesulfonic acid, monohydrate, and 3600 parts of benzene is heated at the boiling point under reflux for 2 hrs., water being removed as formed. Solvent is stripped by vacuum distillation, whereuon the residue is extracted with approximately 2000 parts of warm aqueous sodium bicarbonate. Bicarbonate-insoluble material is taken up in a minimum of hot methanol. The methanol solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, colorless plates of 2,3,4,5-tetrahydro- 4 3-hyhroxy-2-methylsulfonyl-6-phenylpyridazine 3 propionic acid -lactone crystallizes. Isloated by filtration and dried in vacuo at 60-65 it melts at 171-173". It has the formula l I I CH CH COOH EXAMPLE 2 Ethyl 1 methanesulfonamido 5 phenylpyrrole 2- propionate: Approximately parts of l-methanesulfonamido 5 phenylpyrrole 2 propionic acid, 1200 parts of anhydrous ethanol, and approximately 2 parts of concentrated sulfuric acid is heated at the boiling point under reflux for 24 hours, then mixed with approximately 1000 parts of hexane. Decolorizing charcoal is added and the resultant mixture is filtered. From the filtrate, on chilling to around 5", colorless prisms of ethyl l-methanesulfonamido 5 phenylpyrrole 2 propionate precipitate. Collected by filtration and dried in vacuo at 60-65", the product melts at approximately l11-112. It has the formula QUCH cH cooc H EXAMPLE 3 2 butylsulfonyl 2,3,4,5 tetrahydro 3 hydroxy- 6 phenylpyridazine 3 propionic acid 'y-lactone and l-- butanesulfonamido 5 phenylpyrrole 2 propionic acid: A mixture of 94 parts of 4,7 dioxo 7 phenylheptanoic acid, 60 parts of butanesulfonic acid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 3600 parts of benzene is heated at the boiling point under reflux for 3 hours, water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 2000 parts of warm aqueous 5% sodium bicarbonate.

The bicarbonate-insoluble material is 2-butylsulfonyl- 2,3,4,5 tetrahydro 3 hydroxy 6 phenylpyridazine- 3-propionic acid -lactone, having the formula The bicarbonate extract is acidified with 10% hydrochloric acid, and the resultant mixture is extracted with ether. The ether extract is washed with Water, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is 1-butanesulfonamido-S-phenylpyrrole-2-propionic acid, having the formula Nil-$ 0 3 EXAMPLE 4 2,3,4,5 tetrahydro 3 hydroxy 2 methylsulfonyl- 6 (p tolyl)pyridazine 3 propionic acid 'y-lactone and l-methanesulfonamido 5 (p tolyl)pyrrole 2 propionic acid: Substitution of 100 parts of 4,7-dioxo-7-(ptolyl)heptanoic acid and 44 parts of methanesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3 alfords, by the procedure there detailed, 2,3,4,5 tetrahydro 3 hydroxy 2 methylsulfonyl 6 (p tolyl)pyridazine 3 propionic acid 7- lactone, having the formula and l-methanesulfonamido-S-(p-tolyl)pyrrole-2-propionic acid, having the formula mcQ-Ucxgcrgcooa EXAMPLE 5 6 (p flnorophenyl) 2,3,4,5 tetrahydro-3-hydroxy- 2 methylsulfonylpyridazine 3 propionic acid 'y-lactone and 5 (p-fluorophenyl) 1 methanesulfonamidopyrrole- 2-propionic acid: A mixture of 200 parts of 7-(p-tfluorophenyl)-4,7-dioxoheptanoic acid, 88 parts of methane sulfonic acid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 10,800 parts of benzene is heated at the boiling point under reflux for 1 /2 hours, water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 4000 parts of warm aqueous 5% sodium bicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot isopropyl alcohol. They alcohol solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, -6(p-fluorophenyl)-2,3,4,5-tetrahydro 3 hydroxy 2 methylsulfonylpyridazine-3- propionic acid 'y-lactone crystallizes. Isolated by filtration and dried in vacuo at 60-65", it melts at approximately 153-454". It has the formula Ill-$0 03 The bicarbonate extract is acidified with 10% hydrochloric acid, and the mixture which eventuates is extracted with ether. The ether extract is washed with water, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a minimum of hot aqueous methanol. The resultant solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, S-(p-fluorophenyl)-1-methanesulfonamidopyrrole-Z-propionic acid crystallizes. Isolated by filtration and dried in vacuo at 6065, it melts at 168- 170. It has the formula i niso cx EXAMPLE 6 2 butylsulfonyl 6 (p-chlorophenyl) 2,3,4,5-tetrahydro 3 hydroxypyridazine 3 propionic acid -lactone and l butanesulfonamido 5 (p-chlorophenyl)pyrrole- 2-propionic acid: A mixture of 1 08 parts of 7-(p-chlorophenyl)-4,7-dioxoheptanoic acid, 62 parts of butanesulfonic acid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 4500 parts of benzene is heated at the boiling point under reflux for 2 hours, Water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 2000 parts of warm aqueous 5% sodium bicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot isopropyl alcohol. The alcohol solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, 2 butylsulfonyl 6 (p-chlorophenyl) 2,3,4,5 tetrahydro 3 hydroxypyridazine- 3-propionic acid -lactone crystallizes. Isolated by filtration and dried in vacuo at 60-65 it melts at approximately 158-159". It has the formula 1: c1 n-so c 9 o I'IHS 0 0 ,3

EXAMPLE 7 6- (m-bromophenyl) -2-butylsu1fonyl-2,3 ,4,5-tetrahydro- 3-hydroxypyridazine-3-propionic acid 'y-lactone and 1 butanesulfamido-S- (m-bromophenyl)pyrrole-2 propionic acid: Substitution of 124 parts of 7-(m-bromophenyl)- 4,7-dioxoheptanoic acid for the 4,7-dioxo-7-phenylheptanoic acid called for in Example 3 and doubling the amounts of benzene and aqueous bicarbonate prescribed therein affords, by the procedure there detailed, 6-(mbromophenyl)-2-butylsulfonyl-2,3,4,5-tetrahydro 3 hydroxypyridazine-3-pr0pionic acid -lactone, of the formula N-so c n and l-butanesulfonamido-S-(m-bromophenyl)pyrrole 2- propionic acid, of the formula IiIHSO C H N l l CH CH COOH 7 EXAMPLE 8 and l-butanesulfonamido-S- (p-iodophenyl) pyrrole-Z-propionic acid, of the formula IIlHS C H N I CH CH COOH EXAMPLE 9 2,3,4,5-tetrahydro-3-hydroxy-6-(p-methoxyphenyl) 2- methylsulfonylpyridaziue-3-propionic acid 'y-lactone and 5-(p-methoxyphenyl)-1 methanesulfonamidopyrrole 2- propionic acid: Substitution of 212 parts of 7-(p-methoxyphenyl)-4,7dioxoheptanoic acid and 88 parts of methanesulfonic acid hydrazide for the 7-(p-chloropl1enyl)-4,7- dioxoheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 6 and increasing the amounts of benzene and aqueous bicarbonate prescribed therein to 10,800 and 4000 parts, respectively, affords, by the procedure there detailed, 2,3,4,5-tetrahydro-3-hydroxy- 6-(p-methoxyphenyl)-2-methylsulfonylpyridazine 3 pr0- pionic acid -lactone melting at approximately 151-152, of the formula and 5- (p-methoxyphenyl)-1-rnethanesulfonamidopyrrole- 2-propionic acid melting at approximately 191-192", of the formula N moo-@U CHZCHQCOOH EXAMPLE l0 6-(m-ethoxyphenyl)-2,3,4,5-tetrahydro-3 hydroxy 2- methylsulfonylpyridazine-3-propionic acid 'y-lactone and 5-(m-ethoxyphenyl)-1 methanesulfonamidopyrrole 2- propionic acid: Substitution of 112 parts of 7-(m-ethoxyphenyl)-4,7-dioxoheptanoic acid and 44 parts of methanesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide respectively, called for in Example 3 and increasing the amount of benzene prescribed therein from 3600 to 5400 parts alfords, by the procedure there detailed, 6-(m-ethoxyphenyl)-2,3,4,S-tetrahydro-3-hydroxy-2 methylsulfonylpyridazine-3-propionic acid y-lactone of the formula and 5- (m-ethoxyphenyl) l-methanesulfonamidopyrrole- 2-propionic acid, of the formula N I CH CH COOH EXAMPLE 11 2-butylsulfonyl-2,3,4,5-tetrahydro 3 hydroxy-6-(pmethoxyphenyl)pyridazine-3-propionic acid 'y-lactone and l-butanesulfonamido 5 (p-methoxyphenyl)pyrrole-2- propionic acid: Substitution of 106 parts of 7-(p-rnethoxyphenyl)-4,7-dioxoheptanoic acid for the 7-(p-chlorophenyl)-4,7-dioxoheptanoic acid called for in Example 6 and increasing the amount of benzene prescribed therein from 4500 to 5400 parts affords, 'by the procedure there detailed, 2 butylsulfonyl-2,3,4,5-tetrahydro-3-hydroxy-6- (p-methoxyphenyl)pyridazine-3-propionic acid -lactone melting at approximately 110-111", of the formula and l-butanesulfonamido-S- (p-methoxyphenyl pyrrole-Z- propionic acid melting at approximately 169-170", of the formula N R co-GU CH CI-ICOOH EXAMPLE 12 6-(o-fluorophenyl)2,3,4,5-tetrahydro 3 hydroxy 2- phenylsulfonylpyridazine-3-propionic acid -lactone and l-benzenesulfonamido 5 (p-chlorophenyl)pyrrole-2- propionic acid: Substitution of 70 parts of benzenesulfonic acid hydrazide for the butanesulfonic acid hydrazide called for in Example 6 and decreasing the amount of benzene prescribed therein from 4500 to 3600 parts affords, by the procedure there detailed, 6-(p-chlorophenyl-Z,3,4,5-tetrahydro-3-hydroxy 2 phenylsulfonylpyridazine-3-propionic acid 'y-lactone melting as approximately -176", of the formula and l-benzenesulfonamido-S- (p-chlorophenyl pyrrole-2- propionic acid melting at approximately 194-195", of the formula Cl N CH H C COOH EXAMPLE l3 6 (o fluorophenyl)2,3,4,5 tetrahydro 3 hydroxy-Z- phenylsulfonylpyridazine-3-propionic acid 'y-lactone and l-benzenesulfonamido 5 (o-fluorophenyl)pyrrole-Z- propionic acid: Substitution of 102 parts of 7-(ofiuorophenyl)-4,7-dioxoheptanoic acid and 70 parts of benzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3 and increasing the amount of benzene prescribed therein from 3600 to 4500 parts affords, by the procedure there detailed, 6-(o-fluorophenyl)-2,3,4,5-tetrahydro-3-hydroxy 2 phenylsulfonylpyridazine-3-propionic acid 'y-lactone, of the formula and l-benzenesulfonarnido-S-(o-fluorophenyl)pyrrole-Z- propionic acid, of the formula N l I CH2CH2COOH EXAMPLE 14 2,3,4,5 tetrahydro 3 hydroxy 6 (p methoxyphenyl) 2 phenylsulfonylpyradazine 3 propionic acid 'y-lactone and l-benzenesulfonamide 5 (p-methoxyphenyl)pyrrole-Z-propionic acid: Substitution of 132 parts of 7-(p-methoxyphenyl)-4,7-dioxoheptanoic acid and 86 parts of benzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and methanesulfonic acid hydrazide, respectively, called for in Example 1 and increasing the amount of benzene and the reaction time prescribed therein to 4500 parts and 3 hours, respectively, affords, by the procedure there detailed, 2,3,4,5-tetrahydro- S-hydroxy 6 (p methoxyphenyl) 2 phenylsulfonylpyridazine 3 propionic acid -lactone melting at approximately 160-161, of the formula and l-benzenesulfonamido 5 (p methoxyphenyl) pyrrole-Z-propionic acid melting at approximately 154- 155 of the formula H C I I CH CH COOH EXAMPLE 15 Methyl l-benzenesulfonarnido (p-methoxyphenyD- pyrrole-2-propionate: A mixture of 60 parts of l-benzenesulfonamido 5 (p methoxyphenyl)pyrrole-Z-propionic acid, approximately 2 parts of concentrated sulfuric acid, and 1600 parts of methanol is heated at the boiling point under reflux for 5 hours, then diluted with /2 volume of Water. Decolon'zing charcoal is added and the resultant mixture is rapidly heated to the boiling point and filtered hot. From the filtrate, on chilling to around 5, colorless needles of methyl l-benzenesulfonamido-S-(p-methoxyphenyl)pyrrole-2propionate crystallize. Isolated by filtration and dried in vacuo at 60-65, the product melts at 121123. It has the formula H CO I I CH CH C0OCH 10 EXAMPLE 16 6 (m ethoxyphenyl) 2,3,4,5 tetrahydro-3-hydroxy- 2 phenylsulfonylpyridazine 3 propionic acid 'y-lactone and l-benzenesulfonamido 5 (m-ethoxyphenyl)pyrrole- 2-propionic acid: Substitution of 112 parts of 7-(m-ethoxy. phenyl)-4,7-dioxoheptanoic acid and 70 parts of benzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide, respective-- ly, called for in Example 3, and increasing the amount of benzene prescribed therein from 3600 to 4500 parts affords, by the procedure there detailed, 6-(m-ethoxyphenyl)-2,3,4,5-tetrahydro 3 hydroxy-2-phenylsulfonylpyridazine 3 propionic acid 'y-lactone, of the formula and l-benzenesulfonamido 5 (m ethoxyphenyl)- pyrrole-2-propionic acid, of the formula l CHECHECOOH H 0 0 EXAMPLE 17 6 (p fiuorophenyl) 2,3,4,5 tetrahydro-3-hydroxy- 2 (p tolylsulfonyDpyridazine 3 propionic acid 'ylactone and 5-(p-fluorophenyl) 1 (p toluenesulfonamido)pyrrole-Z-propionic acid: A mixture of parts of 7-(p-fiuorophenyl)-4,7-dioxoheptan-oic acid, 74 parts of p-toluenesulfonic acid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 4500 parts of benzene is heated at the boiling point under reflux for 2 hours, water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 2000 parts of Warm aqueous 5% sodium bicarbonate.

The bicarbonate-insoluble material is 6-(p-fluorophenyl)-2,3,4,5-tetrahydro 3 hydroxy 2 (p-tolylsulfonyl) pyridazine-3-propionic acid v-lactone, of the formula The bicarbonate extract is acidified with 10% hydrochloric acid, and the mixture which eventuates is extracted with ether. The ether extract is Washed with water, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is 5-(p-fiuorophenyl)-1- (p-toluenesulfonamido)pyrrole-2-propionic acid melting at approximately -186. It has the formula EXAMPLE 18 6-(m-bromophenyl)-2,3,4,5-tetrahydro 3 hydroxy-2 (o-tolylsulfonyl)pyridazine-3-propionic acid 'y-lactone and S-(m-bromophenyl) 1 (o-toluenesulfonamido)pyrrole- Z-propionic acid: Substitution of 126 parts of 7-(mbromophenyl)-4,7-dioxoheptanoic acid and 74 parts of o-toluenesulfonic acid hydrazide for the 4,7-dioxo-7- phenylheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3 and increasing the 11 amount of benzene prescribed from 3600 to 5400 parts affords, by the procedure there detailed, 6-(m-bromophenyl)-2,3,4,5 tetrahydro-3-hydroxy-2-(o-tolysulfonyl) pyridazine-3-propionic acid 'y-lactone, of the formula and S-(m-bromophenyl) 1 (o-toluenesulfonamido)pyrrole-2-propionic acid, of the formula EXAMPLE 19 6- (p-bromophenyl -2- (p-chlorophenylsulfonyl) -2,3,4,5- tetrahydro-3-hydroxypyridazine 3 propionic acid 'y-lactone and 5 (p-bromophenyl)-1-(p-chlorobenzeuesulfonamido)pyrrole-Z-propionic acid: Substitution of 156 parts of 7-(p-bromophenyl)-4,7-dioxoheptanoic acid and 104 parts of p-chlorobenzenesulfonic acid hydrazide for the 7- (p-chlorophenyl)-4,7-dioxoheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 6 and increasing the amount of benzene prescribed therein from 4500 to 5400 parts affords, by the procedure there detailed, 6-(p-bromophenyl)-2-(p-chlorophenylsulfonyl)-2,3,4,5-tetrahydro 3 hydroxypyridazine-3-propionic acid 'y-lactone melting at approximately 168-169, of the formula and 5 (p-bromophenyl)-1-(p-chlorobenzylsulfonamido) pyrrole-2-propionic acid melting at approximately 209-- 210", of the formula IIIHSO 'QCJ. N Br I I CH CH COOH EXAMPLE 20 6 (o-fluorophenyl)-2-(p-fiuorophenylsulfonyl)-2,3,4,5- tetrahydro 3 hydroxypyridazine-3-propionic acid 'y-lactone and 1-(p-fluorobenzenesulfonamido) 5 (o-fiuorophenyl)pyrrole-Z-propionic acid: Substitution of 102 parts of 7-(o-fluorophenyl)-4,7-dioxoheptanoic acid and 90 parts of p-fiuorobenzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenyl-heptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3 and increasing the amount of benzene prescribed therein from 3600 to 4500 parts affords, by the procedure there detailed, 6-(o-fiuorophenyl) 2 (p-fiuorophenylsulfonyl)- 2,3,4,5 tetrahydro-3-hydroxypyridazine-3-propionic acid -lactone, of the formula and 1- (p-fluorobenzenesulfonamido) -5- (o-fluorophenyl) pyrrole-Z-propionic acid, of the formula I I CH CH 'COOH EXAMPLE 21 2,3,4,5-tetrahydro 3 hydroxy 6 (p-iodophenyl)-2- (p-iodophenylsulfonyl)pyridazine-3-propionic acid 'y-laotone and 1-(p-iodobenzenesulfonamido)-5-(p-iodophenyl)pyrrole-2propionic acid: Substitution of 72 parts of 7-(p-iodophenyl)-4,7-dioxoheptanoic acid and 60 parts of p-iodobenzenesulfonic acid hydrazide for the 4,7-dioxo- 7-phenylheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3 affords, by the procedure there detailed, 2,3,4,5-tetrahydro-3-hydroxy-6- (p-iodophenyl) 2 (p-iodophenylsulfonyl)pyridaZine-3- propionic acid 'y-lactone, of the formula and l (p iodobenzenesulfonamido) 5 (p iodophenyl)pyrrole-Z-propionic acid, of the formula I I CH CH COOH EXAMPLE 22 2-(p-fluorophenylsulfonyl) 2,3,4,5 tetrahydro 3- hydroxy 6 (p-methoxyphenyl)-pyridazine 3 propionic acid 'y-lactone and 1 (p-fiuorobenzenesulfonamido)- 5-(p-methoxyphenyl)pyrrole-Z-propionic acid: A mixture of 126 parts of 7-(p-methoxyphenyl)-4,7-dioxoheptanoic acid, parts of p-fiuorobenzenesulfonic acid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 4500 parts of benzene is heated at the boiling point under reflux for 2 hours, water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 2000 parts of warm aqueous 5% sodium bicarbonate.

The bicarbonate-insoluble material is 2- (p-fluorophenylsulfonyl)-2,3,4,5-tetrahydro 3 hydroxy 6 (pmethoxyphenyl)pyridazine 3 propionic acid -lactone, having the formula The bicarbonate extract is acidified with 10% hydrochloric acid, and the mixture which eventuates is extracted with ether. The ether extract is washed with water, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a minimum of hot aqueous isopropyl alcohol. The resultant solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, 1 (p fluorobenzenesulfonamido) 5 (p methoxyphenyl)pyrrole 2 propionic acid crystallizes. Isolated by filtration and dried in vacuo at 6065, it melts at approximately -171".

It has the formula I CH CH COOH 13 EXAMPLE 23 2 (p bromophenylsulfonyl) '6 (m ethoxyphenyl)- 2,3,4,5 tetrahydro 3 hydroxypyridazine 3 propionic acid 7 lactone and 1 (p bromobenzenesulfonamido)- 5 (m ethoxyphenyl)pyrrole 2 propionic acid: Substitution of 140 parts of 7 (m ethoxyphenyl) 4,7- dioxoheptanoic acid and 126 parts of p-bromobenzenesulfonic acid hydrazide for the 7 (p chlorophenyl)-4,7- dioxoheptanoic acid and butanesulfonic acid hydrazide, respectively called for in Example 6 and shortening the reaction time prescribed therein from 2 to 1% hours affords, by the procedure there detailed, 2 (p bromophenylsulfonyl) 6 (m ethoxyphenyl) 2,3,4,5 tetrahydro 3 hydroxypyridazine 3 propionic acid 7- lactone melting at approximately 169170, of the forand 1 (p bromobenzenesulfonamido) (rn-ethoxyphenyl)pyrrole-2-propionic acid melting at approximately 177-17 8, of the formula 1 CH CH COQH EXAMPLE 24 2 (2,4,5 trichlorophenylsulfonyl) 2,3,4,5 tetrahydro 3 hydroxy 6 (p methoxyphenyDpyridazine- 3 propionic acid 'y-lactone and 1 (2,4,5 trichlorobenzenesulfonamido) 5 (p methoxyphenyl)pyrrole- 2-propionic acid: A mixture of 106 parts of 7 -(p-methoxyphenyl) 4,7 dioxoheptanoic acid, 110 parts of 2,4,5- trichlorobenzenesulfonic acid hydrazide, 1 part of p-toluenesulionic acid monohydrate, and 4500 parts of benzene is heated at the boiling point under reflux for 3 hours, water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 2000 parts of warm aqueous 5% sodium bicarbonate.

The bicarbonate-insoluble material is 2 (2,4,5 trichlorophenylsulfonyl) 2,3,4,5 tetrahydro 3 hydroxy- 6 (p methoxyphenyl)pyridazine 3 propionic acid 'y-lactone, of the formula The bicarbonate extract is acidified with 10% hydrochloric acid, and the mixture which eventuates is extracted with ether. The ether extract is washed with water, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a minimum of hot aqueous isopropyl alcohol. The resultant solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, 1 (2,4,5 trichlorobenzenesulfonamido) 5 (p methoxyphenyl)pyrrole- 2-propionic acid crystallizes. Isolated by filtration and dried in vacuo at 60-65, it melts at approximately 230- 231 It has the formula NHSO C1 EXAMPLE 25 2,3,4,5-tetrahydro 3 hydroxy-6-(2,5-dimethoxyphenyl)-2- (p-methoxyphenylsulfonyl)pyridazine 3 propionic acid 'y-lactone and 1-(p-methoxybenzenesulfonamido)-5- (2,3-dimethoxyphenyl)pyrrole 3 propionic acid: A mixture of 160 parts of 7-(2,5-methoxyphenyl)-4,7-dioxoheptanoic acid [prepared from 2,S-dimethoxyacetophenone and 2-furaldehyde by the procedure described in US. 3,349,091 (Example 1, parts A and B) for the preparation of 7-(o-fiuorophenyl)-4,7-dioxoheptanoic acid], parts of p-methoxybenzenesulfonic acid hydrazide, 1 part of p-toluene-sulfonic acid monohydrate, and 4500 parts of benzene is heated at the boiling point under reflux for 1% hours, water being removed as formed. Solvent is stripped by vacuum distillation, whereupon the residue is extracted with approximately 2000 parts of Warm aqueous 5% sodium bicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot isopropyl alcohol. The alcohol solution is mixed with decolorizing charcoal and then filtered. From the filtrate, on cooling, 2,3,4,5-tetrahydro-3-hydroxy-6- (2,5-dimethoxyphenyl) 2 (p-methoxyphenylsulfonyl) pyridazine-3-propionic acid 'y-lactone crystallizes. Isolated by filtration and dried in vacuo at 60-65 it melts at approximately -161 It has the formula formula i'ms 0 G 00a N I CH CH COOH H CO EXAMPLE 26 6-(m ethoxyphenyl) 2 (p ethoxyphenylsulfonyD- 2,3,4,5-tetrahydro-3-hydroxypyridazine 3 propionic acid v-lactone and l-(p-ethoxybenzenesulfonamido) 5 (methoxyphenyl.) pyrrole 2 propionic acid: Substitution of 112 parts of 7-(m-ethoxyphenyl)-4,7-dioxoheptanoic acid and 88 parts of p-ethoxybenzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3 afiords, by the procedure there detailed 6-(m-ethoxyphenyl) 2 (p ethoxyphenylsulfonyl)-2,3,4,5-tetrahy- 1 5 dro-3-hydroxypyridazine-3-propionic acid 'y-lactone, of the formula and 1 (p ethoxybenzenesulfonamido) (m-ethoxyphenyl)pyrrole-Z-propionic acid, of the formula i mso oc a N I CH CH COOH EXAMPLE 27 6-(p-bromophenyl-2,3,4,5-tetrahydro 3 hydroxy-Z-(pnitrophenylsulfonyl)pyridazine-3-propionic acid 'y-lactone and methyl S-(p-bromophenyl)-1-(p-nitrobenzenesulfonamido)pyrrole-Z-propionate: Substitution of 126 parts of 7-(p-bromophenyl)-4,7-dioxoheptanoic acid and 86 parts of p-nitrobenzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide, respectively, called for in Example 3, increasing the amount of benzene prescribed from 3600 to 4500 parts, and shortening the reaction time to 1 hour affords, by the procedure there detailed, 6-(p-bromophenyl)- 2,3,4,5-tetrahydro 3 hydroxy-Z-(p-nitrophenylsulfonyl) pyridazine-3-propionic acid 'y-lactone, of the formula and S-(p-bromophenyl) 1 (p-nitrobenzenesulfonamido) pyrrole-Z-propionic acid.

The latter product is heated for 2 hours at 9095 with 2300 parts of methanol containing approximately 4 parts of sulfuric acid. From the resultant mixture, on cooling, yellow methyl 5-(p-bromophenyl)-l-(p-nitrobenzenesulfonamido) pyrrole-Z-propionate crystallizes. Isolated by filtration and dried in vacuo at 60-65", is melts at 227- 2302 It has the formula 2 2 i BrUCH CH CO0CH EXAMPLE 28 16 and '5 (o-rfluorophenyD-1-(o-nitrobenzenesulfonamido) pyrrole-Z-propionic acid, of the formula What is claimed is: 1. A compound of the formula wherein Ph represents phenyl optionally substituted by methyl, halogen, or fewer than 3 lower alkoxys and Z represents lower alkyl or phenyl optionally substituted by methyl, lower alkoxy, nitro or fewer than 4 halogens.

2. A compound according to claim 1 having the for- 3. A compound according to claim 1 which is 2,3,4,5- tetrahydro 3 hydroxy-Z-methylsulfonyl-6-phenylpyridazine-3-propionic acid 'y-lactone.

4. A compound according to claim 1 having the formula halogen 5. A compound according to claim 1 which is 6-(pfluorophenyl)-2,3,4,5-tetrahydro 3 hydroxy-2-methylsulfonylpyridazine-3-propionic acid 'y-lactone.

6. A compound according to claim 1 having the formula lower alkoxy N-S 0 r-lower alkyl 7. A compound according to claim 1 which is 2,3,4,5- tetrahydro 3 hydroxy-6-(p-mcthoxyphenyl)-2-methylsulfonylpyridazine-3-propionic acid 'y-lactone.

:1. A compound according to claim 1 having the form a wherein X represents halogen of atomic number less than- 35.

17 9. A compound according to claim 1 which is 6-(pchlorophenyl)-'2,3,4,5-tetrahydro 3 hydroxy-Z-phenylsulfonylpyridazine-3-propionic acid 'y-lactone.

10. LA compound according to claim 1 having the formula lower alkoxy 11. A compound according to claim 1 which is 2,3, 1,5- tetrahydro 3 hydroxy-6-(p-methoxyphenyl)-2-phenylsulfonylpyridazine-3-propionic acid 'y-lactone.

12. -A compound according to claim 1 having the formula halogen halogen 13. A compound according to claim 1 which is 6-(pbromophenyl)-2-(p-chlorophenylsulfonyl) 2,3,4,5 tetrahydro-3-hydroxypyridazine-3-propionic acid v-lactone.

14. A compound according to claim 1 having the formula lower alkoxy N-SOQ-dower alkoxy wherein Ph represents phenyl substituted by fewer than 3 lower alkoxys.

17. A compound according to claim 1 which is 2,'3,4,5- tetrahydro 3 hydroxy- 6-(2,5-dimethoxyphenyl)-2-(pmethoxyphenylsulfonyl)pyridazine 3 propionic acid 7- lactone.

References Cited UNITED STATES PATENTS 3,313,806 4/1967 Nakagome -260-250 A 3,471,495 10/1969 Levine 260-250 A NICHOLAS LS. 'RIZZO, Primary Examiner U.'S. Cl. X.R. 

